Synthesis of new o-quinone methides from β-lapachone analogues

Article abstract of DOI:10.1055/s-0030-1260778

In this work, we synthesized six new o-quinone methides from β-lapachone analogues by treating β-lapachone with acetone and a catalytic amount of iodine under thermal conditions and microwave irradiation. The yields of isolated o-quinone methides ranged f

Full text of DOI:10.1055/s-0030-1260778

LETTER
1623
Synthesis of New o-Quinone Methides from b-Lapachone Analogues
Synthesis of
N
a
ew
o
-Quino
b
ne Methidesrina Baptista Ferreira,a Daniel Tadeu Gomes Gonzaga,a Fernando de Carvalho da Silva,a
Katia Gomes de Lima Araújo,b Vitor Francisco Ferreira*a
a
Universidade Federal Fluminense, Instituto de Química, Departamento de Química Orgânica, 24020-141 Niterói, Rio de Janeiro, Brazil
Fax +55(21)26292362; E-mail: cegvito@vm.uff.br
Universidade Federal Fluminense, Faculdade de Farmácia, Departamento de Bromatologia, CEP 24241-000, Niterói, RJ, Brasil
b
Received 5 April 2011
O
O
Abstract: In this work, we synthesized six new o-quinone methides
from b-lapachone analogues by treating b-lapachone with acetone
and a catalytic amount of iodine under thermal conditions and mi-
crowave irradiation. The yields of isolated o-quinone methides
ranged from 20–80%. During the reactions, the formation of a-pyr-
an naphthoquinones was observed; the yields varied depending
upon the substituent. The reactions using microwave irradiation
were faster, but yields and selectivities did not change significantly.
O
O
O
OH
1
2
O
O
Key words: b-lapachone, ortho-quinone methide, microwave,
isomerization
R2
O
R1
O
O
b-Lapachone (1) is a natural product found as a minority
constituent of the heartwood of trees of the Bignoniaceae
family and is known in Brazil as Ipê.1 It is easily prepared
from the natural product lapachol (2) or by several syn-
thetic methods.2 Due to the variety of microbicidal effects
of this compound, it became a leading structure in medic-
inal chemistry, and various synthetic methods were ex-
plored, such as transformations of the carbonyls to mono-
and disubstituted derivatives3 and ortho-quinone me-
thides (o-QM). To this effect, in our preliminary commu-
nication of this work, we reported the synthetic
methodology for several stable o-QM 3a–e (Figure 1)
from b-lapachone (1),4 which in most cases are short-lived
intermediates that are involved in various biological pro-
cesses and that have wide applicability in organic synthe-
sis.5
R1
O
R2
3a R1 = Me, R2 = H
3b R1 = R2 = Me
R3
3c R1 = c-Pr, R2 = H
4
3d R1 = Me, R2 = CO2Et
3e R1 = EtO2CCH2, R2 = H
Figure 1 Structure of lapachone (1), its precursor lapachol (2),
ortho-quinone methides 3, and b-lapachone analogues 4
The b-pyran naphthoquinones 4a–g were treated with ac-
etone, and a catalytic amount of iodine and were heated
thermally and exposed to microwave irradiation to pro-
duce a mixture, which after separation on silica gel, fur-
nished the o-QM 9a–g in varying yields (Table 1). The
structures of 9a–g were assigned by infrared (IR) spec-
troscopy and H NMR and 13C NMR analysis. In the IR
1
Continuing our interest in the synthesis of o-QM, we de-
cided to study the transformation of several b-lapachone
analogues 4 into stable ortho-quinone methides by ther-
mal heating and using microwave irradiation.
spectrum, only one absorption band corresponding to a
carbonyl group (1585–1590 cm–1) was observed. The
structures were confirmed by 1H NMR and 13C NMR us-
ing 2D NMR techniques, such as COSY, HSQC, HMBC,
and NOESY. For example, in 9a, it is possible to clearly
confirm that the exocyclic olefin was formed at the C-6
carbonyl due to the correlation between H-13 and H-7 in
the NOESY spectrum. This result also confirms that its
configuration can be securely assigned as E.
The preparation of the b-lapachone analogues 4a–g was
carried out in one step using an improved synthetic proto-
col recently reported by our group.6 The Knoevenagel
condensation of lawsone (5) with paraformaldehyde
forms the o-QM intermediate 6, which upon intermolecu-
lar hetero Diels–Alder cycloaddition with styrene deriva-
tives 7a–g led to a- and b-pyran naphthoquinones 8a–g
and 4a–g, respectively, in good overall yield. The a- and
b-isomers were separated by column chromatography us-
ing silica gel adsorbent in the yields outlined in Scheme 1.
Analyses of the secondary product in these reactions
prove that they are a-pyran naphthoquinones 8a–g, a
product that originates from the isomerization of b-pyran
naphthoquinones 4a–g, as shown in Scheme 2.
The formation of the o-QM 9a–g and the a-isomers 8a–g
1
were quantified by H NMR analysis of that crude mix-
tures that were obtained by thermal heating and micro-
SYNLETT 2011, No. 11, pp 1623–1625
Advanced online publication: 10.06.2011
x
x
.x
x
.2
0
1
1
DOI: 10.1055/s-0030-1260778; Art ID: S07511ST
© Georg Thieme Verlag Stuttgart · New York

1624
S. B. Ferreira et al.
LETTER
R1
R2
R2
R3
O
O
O
O
O
O
O
O
R3
R2
OH
O
R1
O
7a–g
H
H
+
R1
O
EtOH–H2O (1:1)
Δ, 5–8 h
R3
O
8a R1 = R2 = R3 = H, 75%
4a R1 = R2 = R3 = H, 23%
5
6
8b R1 = R2 = H, R3 = F, 74%
8c R1 = R2 = H, R3 = Cl, 73%
8d R1 = R2 = H, R3 = Br, 58%
8e R1 = R2 = H, R3 = Me, 75%
8f R1 = Me, R2 = R3 = H, 70%
8g R1 = H, R2 = R3 = Me, 80%
4b R1 = R2 = H, R3 = F, 26%
4c R1 = R2 = H, R3 = Cl, 25%
4d R1 = R2 = H, R3 = Br, 19%
4e R1 = R2 = H, R3 = Me, 20%
4f
R
1 = Me, R2 = R3 = H, 15%
4g R1 = H, R2 = R3 = Me, 17%
Scheme 1 Preparation of a- and b-pyranaphthoquinones 8a–g and 4a–g
Table 1 o-QM 9a–g Obtained under Thermal and Microwave
Reactions
Table 2 Analysis of Crude Mixtures by 1H NMR of the Reactions
Carried on Thermal and Microwave Conditions
Entry
Product 9 R1
R2
R3
Yield
(%)a
Yield
(%)b
Entry
R1
H
R2
H
R3
H
Ratio of 9/8a Ratio of 9/8b
1
2
3
4
5
6
7
95:5
98:2
1
2
3
4
5
6
7
9a
9b
9c
9d
9e
9f
H
H
H
70
60
45
45
20
40
0
80
65
58
52
40
48
0
H
H
F
96:4
99:1
H
H
F
H
H
Cl
Br
Me
H
87:13
44:56
40:60
45:55
0:100
95:5
H
H
Cl
Br
Me
H
H
H
52:48
48:52
56:44
0:100
H
H
H
H
H
H
Me
H
H
Me
H
H
Me
Me
9g
Me
Me
a Conventional heating.
b Microwave irradiation, reaction time: 10 min.
a Conventional heating, reaction time: 12 h.
b Microwave irradiation, reaction time: 10 min.
catalytic iodine to the C-6 carbonyl leads to the formation
of the o-QM 9a–g and competes with the pyran ring open-
ing to a benzylic carbenium ion and then closing to the a-
isomers 8a–g (Scheme 3). This hypothesis is confirmed
by observing the stabilization of the carbenium ion inter-
mediate caused by the electronic effects of the aromatic
ring. A more stable carbenium ion leads to increased for-
mation of the a-isomer (entries 4–7 in Table 2). In the
case of entry 7 (Table 2), 8g was obtained quantitatively.
Electron-withdrawing groups increased the yield of the
o-QM (entries 2–4).
wave irradiation. The aromatic proton signals of H-7 and
H-10 that corresponded with the o-QM (9) and the a-iso-
mer byproducts 8, respectively, were selected for this
analysis, and ratios of 10:8 for compounds are described
in Table 2.
The overall yields of the reactions under microwave irra-
diation were higher than the thermal reactions and run for
a shorter time period, but ratios 11:9 of the products re-
mained comparatively the same. These results can be ra-
tionalized considering that the addition of acetone and
O
R2
R3
O
O
O
O
O
O
I2, acetone
+
R1
reflux, 70 °C
or MW
O
O
R1
8a–g
R1
R2
R2
R3
9a–g
R3
4a–g
Scheme 2 Reaction of b-pyran naphthoquinones 4a–g with acetone catalyzed by iodine
Synlett 2011, No. 11, 1623–1625 © Thieme Stuttgart · New York

LETTER
Synthesis of New o-Quinone Methides
1625
O
O
R3
O
O
O
••
I2
O
+
R1
R2
O
O+
O
I–
••
I
O
I
R1
R1
R2
R2
R3
R3
R3
O
O
I2
O
O
O
R1
R2
O
O
8a–g
R1
R2
R3
9a–g
Scheme 3 Proposed mechanism for formation of 9a–g and 8a–g
Castro, S. L.; Pinto, A. V. Arzneim.-Forsch./Drug Res. 2000,
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This study showed that other analogues of b-lapachone
could be used for the synthesis of a new stable o-QM.
However, in the studied reactions, it was observed that the
pyran ring is not stable and can be opened to produce the
a-pyran naphthoquinone isomers. The results clearly
show that the stabilization of the carbenium ion interme-
diates increases the formation of a-isomers. The reactions
under microwave irradiation were faster, but the yields
and selectivities did not change significantly.
(2) (a) Fieser, L. F.; Fieser, M. J. Am. Chem. Soc. 1948, 70,
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
Thanks are due to the CNPQ (National Council of Research of Bra-
zil), CAPES and FAPERJ-PRONEX (E-26/171.512.2010), for fun-
ding this work. S. B. Ferreira thanks CAPES-PNPD for her doctoral
fellowship. The authors thank Dr. Rodrigo Octavio Mendonça
Alves de Souza, from Universidade Federal do Rio de Janeiro for
providing the microwave used for the synthesis.
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Synlett 2011, No. 11, 1623–1625 © Thieme Stuttgart · New York